Project 1: Adolescents' use of amphetamine drugs is a major public health concern, as 11% of high school seniors have used methamphetamine or a pharmaceufical amphetamine taken other than for prescribed purposes (MTF, 2008). Interoception refers to sensing and processing the internal body state via afferent Cfibers, which is integrated in the insular cortex. Previous invesfigafions have linked insular cortex functioning to aspects of addiction. However, the precise role of the interoceptive system and insular cortex in the development of substance dependence is unclear. Here, we hypothesize that the insular cortex is hyporesponsive to interoceptive stimulation, but hyper-reactive to drug cues in adolescents at risk for substance dependence based on repeated experimentation during youth. In this project, we will compare activity of the interoceptive system in response to positively and negatively valenced interoceptive and drug cue stimuli between: (1) at-risk adolescents who are current users of amphetamines, (2) resilient adolescents who are former users of amphetamines but stopped without ever meeting dependence criteria, and (3) control adolescents with no history of amphetamines use. The aims are: (1) to determine the role of the insula in processing interoceptive information in teens at risk for amphetamine dependence, teens who appear resilient to amphetamine dependence, and healthy control adolescents; (2) to determine the role of the insula in processing cue-related informafion in teens at risk for amphetamine dependence, teens who have been resilient to amphetamine dependence, and healthy control adolescents; (3) to modify neuroimaging paradigms in response to Project 3 (animal studies) to better characterize the role of interoceptive circuitry in the direct posifive (high) versus negafive (withdrawal/hangover) effects among teens at risk for amphetamine dependence; and (4) examine the development of the interoceptive system in adolescence by comparing adolescent controls and adult controls (from Project 2) on activation patterns to interoceptive and drug cue tasks. Together, these studies will help determine how interoceptive dysregulation plays a role in putting adolescents at risk for amphetamine use. These insights will be used in future studies aimed at altering the reactivity of the insular cortex as a way of preventing or treating substance dependence. Combining results from Projects 1 and 2 will yield important insights into the role of the insular cortex and interocepfive functioning in risk for amphetamine dependence in general. Finally, the outcome of this study will prepare us for longitudinal studies of interoceptive dysfunction in a P50 extension of this Center.